Numerous pharmaceutical compounds are preferentially delivered by means of metered dose inhalation (MDI) devices, in which a physiologically inert propellant of high vapor pressure is used to discharge a precise amount of medication with each operation. These MDI devices, also known as aerosols or inhalers, have found widespread use among patients suffering, for example, from episodic or chronic asthma. The propellants of choice have historically been chlorofluoro-carbons, such Propellant 11 (trichlorofluoromethane), Propellant 12 (dichlorodifluoromethane) and Propellant 114 (dichlorotetrafluoroethane).
In recent years, however, there have been growing concerns that chlorofluorocarbon (CFC) propellants have detrimental environmental effects, and in particular that they interfere with the protective upper-atmosphere ozone layer. Under an international accord (the Montreal Protocol), the use of CFC propellants will be prohibited by the start of the year 2000, and possibly sooner. Alternative propellant vehicles are being developed which exhibit little or no ozone depletion potential (ODP). Such alternative propellants include two--HFC-134a (1,1,1,2-tetrafluoroethane) and HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane)--which have negligible ODP and are currently undergoing safety and environmental testing.
Unfortunately, many surfactants which are generally used in known MDI formulations have been found to be imiscible, and therefore incompatible, with these new, non-CFC propellants. Such surfactants are necessary to prevent aggregation (in the form of "caking" or crystallization, for example) of the medicinally active compound in the reservoir of the inhaler, to facilitate uniform dosing upon aerosol administration, and to provide an aerosol spray discharge having a favorable respirable fraction (that is, a particle size distribution such that a large portion of the discharge reaches the alveoli where absorption takes place, and thus produces high lung deposition efficiencies). To overcome this incompatibility, it has previously been taught to include cosolvents (such as ethanol) with the non-CFC propellants so as to blend the surfactants into the formulation. Another suggested approach has been to emulsify the MDI formulation in the presence of a surfactant with low-vapor pressure additives, such as polyhydroxy alcohols as for example propylene glycol.
Such cosolvents or additives may of course be physiologically active, and in some instances may not be tolerated by the user of an MDI medication. There is therefore a need for MDI formulations compatible with non-CFC, non-ozone depleting propellants, which prevent aggregation of drug particles without the use of cosolvents or similar carrier additives, and which provide uniformity of dosing and a favorable respirable fraction.
Surprisingly, it has now been found that polyglycolyzed glycerides, as for example Labrafac.RTM. CM 6, Labrafil.RTM. WL 2609 BS, Labrafac.RTM. CM 8, Labrafac.RTM. CM 10, Labrafil.RTM. M 10, Labrafil.RTM. NA 10, Labrafac.RTM. CM 12, Labrasol.RTM. (Labrafac.RTM. CM 14) and the like are capable of stabilizing MDI formulations utilizing non-ozone depleting propellants such as HFC-134a and HFC-227ea so as to (i) prevent aggregation, (ii) provide dosing uniformity, and (iii) afford high lung deposition efficiency without the need for either surfactants or cosolvents. Additionally, the polyglycolyzed glycerides have the unexpected benefit of providing adequate lubrication for the valve used in an MDI product without the need for additional lubricants, thus aiding reliable functioning of the aerosol device throughout the life of the product.
Significant characteristics of such polyglycolyzed glycerides used are that: (i) they are non-ionic surface active agents which do not chemically interact with drug; (ii) they have been used previously in oral drug delivery liquid dosage form, thereby establishing their physiological acceptability; (iii) their hydrophilic lipophilic balance (HLB) values are much higher than sorbitan trioleate (SPAN 85), ranging in the case of Labrafac.RTM. from 6 to 14 and in the case of Labrafil.RTM. products of interest from 6 to 10 (compared to 4 for SPAN 85); and (iv) they are highly soluble in HFC 134a. Non-CFC formulations which include polyglycolyzed glycerides do not require the addition of (i) cosolvents like ethanol to blend the surfactant into the formulation, (ii) conventional surfactants such as sorbitan trioleate (SPAN 85), sorbitan monooleate and oleic acid, or (iii) protective colloids like sodium lauryl sulfate, cholesterol and palmitic acid, yet provide high lung deposition efficiencies and respirable fractions comparable to those obtained with known CFC-propellant formulations. It is thus expected that non-CFC formulations comprising polyglycolyzed glycerides will be useful for the delivery of both peptide and non-peptide pharmaceutical medicaments for which MDI delivery is deemed preferable.